S180: RESULTS OF A PHASE 3 TRIAL OF AN ORAL CXCR4 ANTAGONIST, MAVORIXAFOR, FOR TREATMENT OF PATIENTS WITH WHIM SYNDROME
Authors: Raffaele Badolato, Jean Donadieu
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency presenting with leukopenia and infections, predominately caused by gain-of-function variants in CXCR4. Mavorixafor, an investigational oral CXCR4 antagonist, demonstrated promising efficacy and safety profiles in a phase 2 trial for participants with WHIM syndrome. Aims: To report results of the randomized, double-blind, multicenter, placebo-controlled period of a phase 3 study evaluating the efficacy and safety of mavorixafor in participants with WHIM syndrome (NCT03995108). Methods: Participants aged ≥12 years with clinical diagnosis of WHIM syndrome, confirmed CXCR4 variant, and absolute neutrophil count (ANC) or total white blood cell (WBC) count ≤400 cells/µL at screening were eligible. Written informed consent was provided by or for all participants prior to initiating the study. Specifically, a parent or guardian provided signed informed consent for minor participants (<18 years of age globally, <16 years of age in the Netherlands and other applicable regions), who additionally provided signed assent to participate in the trial. Participants were randomized 1:1 to receive mavorixafor (>50 kg, 400 mg once daily [QD]; ≤50 kg, 200 mg QD) or placebo for 52 weeks. The primary endpoint was time above threshold ANC (TATANC). Figure 1 shows study design and select secondary endpoints. Results: Overall, 31 participants were randomized (mavorixafor, n=14; placebo, n=17) and received ≥1 dose of treatment (intent-to-treat population). The primary endpoint, mean TATANC, was 15.04 (mavorixafor-group) vs 2.75 hours (placebo-group; P<.0001). Additionally, mean TAT absolute lymphocyte count (TATALC) was 15.80 (mavorixafor-group) vs 4.55 hours (placebo-group; P<.0001). Mean absolute WBC count, ANC, and ALC increased from baseline into normal range and sustained at each timepoint assessed over 52 weeks with mavorixafor versus placebo. Compared with placebo-group, mavorixafor-group showed 60% lower annualized infection rate (least squares [LS] mean: mavorixafor, 1.7; placebo, 4.2; nominal P=.0072), and 40% lower total infection score, a combination of infection number and severity (LS mean [95% CI]: mavorixafor, 7.41 [1.64–13.19]; placebo, 12.27 [7.24–17.30]). Greater reduction in infection duration and type and antibiotic use was observed with mavorixafor versus placebo. No discontinuations occurred due to adverse events (AEs). No treatment-related serious AEs or treatment-limiting toxicities were observed. Summary/Conclusion: Primary and first key secondary endpoints were met. Mavorixafor-group showed significantly higher mean TATANC and TATALC and greater reduction in infection frequency, severity, and duration versus placebo-group. Mavorixafor was generally well tolerated over the 52-week treatment period. About 87% of eligible participants enrolled in the open-label extension.Keywords: Neutropenia, CXCR4, Immunodeficiency, Phase III